WO2014100639A1 - Administration transmucosale d'acétate de glatiramère - Google Patents

Administration transmucosale d'acétate de glatiramère Download PDF

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Publication number
WO2014100639A1
WO2014100639A1 PCT/US2013/077034 US2013077034W WO2014100639A1 WO 2014100639 A1 WO2014100639 A1 WO 2014100639A1 US 2013077034 W US2013077034 W US 2013077034W WO 2014100639 A1 WO2014100639 A1 WO 2014100639A1
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WO
WIPO (PCT)
Prior art keywords
percent
present
oral tablet
tablet
weight
Prior art date
Application number
PCT/US2013/077034
Other languages
English (en)
Inventor
Ursula GEISTER
Stephan Schweizer
Martina BUERGER
Ralph Stefan
Gerald Huber
Tanja PRIES
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2013361053A priority Critical patent/AU2013361053A1/en
Priority to SG11201504422XA priority patent/SG11201504422XA/en
Application filed by Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to BR112015014095A priority patent/BR112015014095A2/pt
Priority to US14/653,022 priority patent/US20160193276A1/en
Priority to EP13865051.0A priority patent/EP2934492A4/fr
Priority to CA2895359A priority patent/CA2895359A1/fr
Priority to KR1020157019729A priority patent/KR20150111918A/ko
Priority to EA201591188A priority patent/EA201591188A1/ru
Priority to CN201380067083.XA priority patent/CN104869983A/zh
Priority to JP2015549792A priority patent/JP2016503803A/ja
Priority to MX2015007678A priority patent/MX2015007678A/es
Publication of WO2014100639A1 publication Critical patent/WO2014100639A1/fr
Priority to IL239280A priority patent/IL239280A0/en
Priority to ZA2015/05049A priority patent/ZA201505049B/en
Priority to HK16102020.2A priority patent/HK1214134A1/zh
Priority to HK16102544.9A priority patent/HK1214523A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • MS Multiple Sclerosis
  • CNS central nervous system
  • MS has also been classified as an autoimmune disease.
  • MS disease activity can be monitored by magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses.
  • MRI magnetic resonance imaging
  • Benign multiple sclerosis is a retrospective diagnosis which is characterized by 1-2 exacerbations with complete recovery, no lasting disability and no disease progression for 10-15 years after the initial onset. Benign multiple sclerosis may, however, progress into other forms of multiple sclerosis.
  • SPMS Secondary Progressive Multiple Sclerosis
  • SPMS may evolve from RRMS. Patients afflicted with SPMS have relapses, a diminishing degree of recovery during remissions, less frequent remissions and more pronounced neurological deficits than RRMS patients. Enlarged ventricles, which are markers for atrophy of the corpus callosum, midline center and spinal cord, are visible on MRI of patients with SPMS.
  • PPMS Primary Progressive Multiple Sclerosis
  • PPMS is characterized by a steady progression of increasing neurological deficits without distinct attacks or remissions. Cerebral lesions, diffuse spinal cord damage and evidence of axonal loss are evident on the MRI of patients with PPMS.
  • Chronic progressive multiple sclerosis is a term used to collectively refer to SPMS, PPMS, and PRMS (Types of Multiple Sclerosis (MS), 2005, ⁇ themcfox.com/multiple-sclerosis/types- of-ms/types-of-multi-ple-sclerosis . htm>) .
  • the relapsing forms of multiple sclerosis are SPMS with superimposed relapses, RRMS and PRMS.
  • a clinically isolated syndrome is a single monosymptomatic attack compatible with MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS) .
  • Multiple sclerosis may present with optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control) , impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning.
  • Glatiramer acetate (GA) , a mixture of polypeptides which do not all have the same amino acid sequence, is marketed under the tradename Copaxone®.
  • GA comprises the acetate salts of polypeptides containing L-glutamic acid, L-alanine, L-tyrosine and L-lysine at average molar fractions of 0.141, 0.427, 0.095 and 0.338, respectively.
  • the average molecular weight of Copaxone® is between 5,000 and 9,000 daltons.
  • glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L- lysine, L-tyrosine, acetate (salt) .
  • CAS-147245-92-9 Copaxone® (“Copaxone", Full Prescribing Information, (February, 2009), FDA Marketing Label) (20mg glatiramer acetate daily injection) is an approved therapy for patients with relapsing remitting multiple sclerosis (RRMS) , including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.
  • GA has also been disclosed for use in the treatment of other autoimmune diseases (U.S. Patent Publication No. 2002/0055466 Al (R. Aharoni et al . ) , inflammatory non-autoimmune diseases (U.S. Patent Publication No. 2005/0014694 Al (V. Wee Yong et al.); and U.S. Patent Application No. 2002/0077278 Al, published Jun . 20, 2002 (Young et al . ) ) and other diseases (U.S. Patent Publication Nos. 2003/0004099 Al and 2002/0037848 Al (Eisenbach-Schwartz, et al . ) ; U.S. Pat. No. 6, 514, 938 Bl, issued Feb.
  • the 20mg/day subcutaneous (s.c.) dose has been shown to reduce the total number of enhancing lesions in MS patients as measured by MRI (G. Comi et al . , European/Canadian Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of the Effects of Glatiramer Acetere on Magnetic Resonance Imaging-Measured Disease Activity and Burden in Patients with Relapsing Multiple Sclerosis, Ann. Neurol. 49:290-297 (2001) ) .
  • IPIR Immediate Post-Injection Reaction
  • Glatiramer Acetate Injection Glatiramer acetate administration through ingestion or inhalation has been disclosed (U.S. Patent 6,214,791); and compositions for oral, nasal and pulmonary administration also have been disclosed (U.S. Patent Application Publication No. 2001/0055568 Al) .
  • mice showed that orally administered glatiramer acetate inhibited the induction of experimental autoimmune encephalomyelitis (EAE) in rats and mice and suggested that oral administration of glatiramer acetate may modulate multiple sclerosis as well (Teitelbaum et al . , Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1, Immunology 96:3842-3847 (1999)) .
  • alternative routes of administration have yet to be demonstrated to be effective in the treatment of multiple sclerosis.
  • glatiramer acetate administered orally did not affect relapse rate or other clinical MRI parameters of disease activity in a recent clinical trial (Filippi et al, Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study, Lancet Neurol. 5(3) :213-220 (2006)) .
  • Buccal administration avoids hepatic metabolism and gastrointestinal degradation which can hinder effectiveness of orally administered drugs and provides an attractive alternative to oral administration.
  • the buccal mucosa is not an absorptive organ and permeation of the drug to be administered is problematic.
  • Other problems to be overcome include drug stability and formulation palatability.
  • Drugs administered via oral mucosa offers several ad-vantages ⁇ Ease of administration.
  • intestine can be administered by this route.
  • This route provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes, cardiovascular agents etc.
  • the buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin.
  • the present invention provides an oral tablet comprising glatiramer acetate in an amount from about 10 percent to about 60 percent by weight and one or more gel forming agents in a total amount up to about 90 percent by weight.
  • the present invention provides an oral tablet comprising glatiramer acetate in an amount from about 10 percent to about 40 percent by weight and one or more gel forming agents in a total amount up to about 90 percent by weight.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg carbomer, about 25 mg hydroxypropylcellulose, about 30.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 50 mg carbomer, about 15 mg hydroxypropylcellulose, about 12 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg chitosan, about 45 mg hydroxypropylcellulose, about 10.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 45 mg chitosan, about 30 mg hydroxypropylcellulose, about 2 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg thiolated chitosan, about 45 mg hydroxypropylcellulose, about 10.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 45 mg thiolated chitosan, about 30 mg hydroxypropylcellulose, about 2 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg thiolated carbomer, about 25 mg hydroxypropylcellulose, about 30.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 50 mg thiolated carbomer, about 15 mg hydroxypropylcellulose, about 12 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 50 mg glatiramer acetate, about 40 mg carbomer, about 10 mg hydroxypropyl cellulose, about 47 mg mannitol, about 1 mg fumed silica and about 2 mg sodium stearyl fumerate.
  • the present invention also provides a method of delivering glatiramer acetate across a buccal membrane comprising orally administering an oral tablet of any one of the embodiments .
  • the present invention also provides a process of making a pharmaceutical composition containing glatiramer acetate, comprising the steps of: a) mixing the glatiramer acetate with one of more excipients under dry conditions; and
  • Figure 1 shows a buccal tablet prepared according to Example 7 which has been placed on glass in a small amount of water for two hours to simulate conditions in the buccal pouch.
  • Figure 2 shows the average permeation of the different formulations. Data series are presented as follows: tablets (diamond markers) , glatiramer acetate solution without pre-incubated tissue (square markers, solid line) and glatiramer acetate solution with DMSO pre-incubated tissue (square markers, dotted line) .
  • an “amount” or “dose” of an agent measured in milligrams refers to the milligrams of agent present in a drug product, regardless of the form of the drug product.
  • Administration of different amounts of glatiramer acetate using oral tablet of the present invention can be accomplished by using one, two, three, four or five oral tablets at the same time or consecutively or by using a portion of an oral tablet.
  • 1 ⁇ 2 of an oral tablet can be obtained by cutting an oral tablet once and 1 ⁇ 4 of an oral tablet can be obtained by cutting an oral tablet twice.
  • Administration of an amount from about 5 to about 200 mg of glatiramer acetate can be achieved using the oral tablets of the present invention.
  • administration of 5 mg glatiramer acetate can be accomplished by using 1 ⁇ 4 of an oral tablet containing 20 mg glatiramer acetate and administration of 10 mg glatiramer acetate can be accomplished by using 1 ⁇ 2 of an oral tablet containing 20 mg glatiramer acetate.
  • administration of 20, 40, 60, 80 or 100 mg glatiramer acetate can be accomplished by using 1, 2, 3, 4 or 5 oral tablets containing 20 mg glatiramer acetate, respectively.
  • administration of 25 mg glatiramer acetate can be accomplished by using 1 ⁇ 2 of an oral tablet containing 50 mg glatiramer acetate and administration of 50, 100, 150 or 200 mg glatiramer acetate can be accomplished using 1, 2, 3 or 4 oral tablets containing 50 mg glatiramer acetate acetate, respectively.
  • administration of 100 mg glatiramer acetate can be accomplished, for example, by using a single oral tablet containing 100 mg glatiramer acetate, or by using 2 oral tablets containing 50 mg glatiramer acetate, etc.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient ( s ) and the inert ingredient ( s ) that make up the carrier, as well as any product which results, directly or indirectly from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • gel forming agents are agents which form a matrix which allows for controlled release of an active ingredient.
  • Gel forming agents include, but are not limited to, carbomer, carbomer (sodium salt) , hydroxypropylcellulose, chitosan, thiolated chitosan, thiolated carbomer, ethylcellulose, gelatine, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, gummi arabicum, xanthan gum and carrageen.
  • Gel forming agents are commercially available under numerous trade names. For example, hydroxypropyl cellulose is available as Klucel ® or Klucel ® HF.
  • glidants are agents which improve flow in a powdered mixture.
  • Glidants include, but are not limited to, colloidal silicon dioxide colloidal silicon dioxide, a fumed silica, a hydrophobic fumed silica such as Aerosil ® or Aerosil ® 200 a magnesium aluminometasilicate such as Neusilin ® and magnesium stearate.
  • lubricants include, but are not limited to a stearate, a stearyl fumerate such as sodium stearyl fumerate or Pruv ®, talcum powder or fatty acid, glycerol dibehenate, more preferably, hexanedioic acid or an earth alkali metal stearate, such as magnesium stearate.
  • an "oral tablet” is a tablet designed to be administered in the oral cavity, it includes tablets designed to be administered between the cheek and gum and tablets designed to be administered sublingually .
  • the oral tablet is a mucoadhesive oral tablet.
  • Carbomers are synthetic high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol . They contain between 52% and 68% of carboxylic acid (COOH) groups calculated on the dry basis.
  • the BP 2009 and PhEur 6.4 have a single monograph describing carbomer; the USP32-NF27 contains several monographs describing individual carbomer grades that vary in aqueous viscosity, polymer type, and polymerization solvent.
  • the molecular weight of carbomer is theoretically estimated at 7 x 10 5 to 4 x 10 9 .
  • Carbomers are commercially available under numerous trade names. For example, Carbopol ® or Carbopol ® 974 P.
  • relapsing MS includes:
  • relapsing forms of multiple sclerosis include: Relapsing-remitting multiple sclerosis (RRMS) , characterized by unpredictable acute episodes of neurological dysfunction (relapses) , followed by variable recovery and periods of clinical stability;
  • RRMS Relapsing-remitting multiple sclerosis
  • SPMS Secondary Progressive MS_
  • PRMS Primary progressive-relapsing multiple sclerosis
  • PRMS progressive-relapsing multiple sclerosis
  • the present invention provides an oral tablet comprising glatiramer acetate in an amount from about 10 percent to about 60 percent by weight and one or more gel forming agents in a total amount up to about 90 percent by weight.
  • the present invention provides an oral tablet comprising glatiramer acetate in an amount from about 10 percent to about 40 percent by weight and one or more gel forming agents in a total amount up to about 90 percent by weight.
  • the glatiramer acetate is present in an amount from about 15 percent to about 30 percent by weight.
  • the glatiramer acetate is present in an amount from about 17 percent to about 25 percent by weight.
  • the glatiramer acetate is present in an amount from about 20 percent to about 23 percent by weight.
  • the glatiramer acetate is present in an amount from about 15 percent to about 50 percent by weight.
  • the glatiramer acetate is present in an amount from about 25 percent to about 40 percent by weight. In one or more embodiments of the present invention, the glatiramer acetate is present in an amount from about 30 percent to about 35 percent by weight.
  • the glatiramer acetate is present in an amount of about 33 percent by weight.
  • the glatiramer acetate is present in an amount of about 20 percent by weight.
  • the glatiramer acetate is present in an amount of about 22 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 20 percent to about 90 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 40 percent to about 90 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 50 percent to about 80 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 55 percent to about 75 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 20 percent to about 40 percent by weight.
  • the one or more gel forming agents are present in a total amount from about 30 percent to about 35 percent by weight.
  • the one or more gel forming agents are present in a total amount of about 33 percent by weight. In one or more embodiments of the present invention, the oral tablet further comprises a filler present in an amount up to about 80 percent by weight.
  • the filler is present in an amount up to about 60 percent by weight .
  • the filler is present in an amount up to about 50 percent by weight .
  • the filler is present in an amount up to about 40 percent by weight .
  • the filler is present in an amount up to about 20 percent by weight .
  • the filler is present in an amount from about 2 percent to about 17 percent by weight.
  • the filler is present in an amount from about 15 percent to about 50 percent by weight.
  • the filler is present in an amount from about 25 percent to about 40 percent by weight.
  • the filler is present in an amount from about 30 percent to about 35 percent by weight.
  • the filler is present in an amount of about 31 percent by weight .
  • the oral tablet further comprises a glidant present in an amount up to about 3 percent by weight.
  • the glidant is present in an amount from about 0.5 percent to about 1.5 percent by weight.
  • the glidant is present in an amount from about 0.75 percent to about 1.25 percent by weight.
  • the glidant is present in an amount from about 0.3 percent to about 1.0 percent by weight. In one or more embodiments of the present invention, the glidant is present in an amount from about 0.6 percent to about 0.8 percent by weight.
  • the glidant is present in an amount of about 0.7 percent by weight.
  • the oral tablet further comprises a lubricant present in an amount up to about 10 percent by weight.
  • the lubricant present in an amount up to about 5 percent by weight .
  • the lubricant is present in an amount from about 1 percent to about 3 percent by weight. In one or more embodiments of the present invention, the lubricant is present in an amount from about 1 percent to about 1.5 percent by weight.
  • the lubricant is present in an amount of about 1.3 percent by weight .
  • the lubricant is present in an amount from about 1.5 percent to about 2 percent by weight.
  • the one or more gel forming agents are selected from the group consisting of carbomer, carbomer (sodium salt) , hydroxypropylcellulose, chitosan, thiolated chitosan, thiolated carbomer, ethylcellulose, gelatine, hydroxyethy1cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethlcellulose, gummi arabicum, xanthan gum, carboxymethyl cellulose and carrageen .
  • the one or more gel forming agents are selected from the group consisting of carbomer, hydroxypropylcellulose, chitosan, thiolated chitosan, thiolated carbomer, ethylcellulose, gelatine, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, gummi arabicum, xanthan gum, carboxymethyl cellulose and carrageen.
  • the filler is selected from the group consisting of mannitol, lactose, saccharose, sucrose, dextrose, isomalt, sorbitol, calcium phosphate, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, glucopyranosyl mannitol and calcium sulfate.
  • the filler is mannitol.
  • the mannitol is Parteck ® M or Parteck ® M 200.
  • the glidant is selected from the group consisting of silicon dioxide, colloidal silicon dioxide, a fumed silica, a hydrophobic fumed silica, a magnesium aluminometasilicate such as Neusilin ® and magnesium stearate.
  • the glidant is selected from the group consisting of silicon dioxide, colloidal silicon dioxide, Neusilin and magnesium stearate .
  • the lubricant is selected from the group consisting of sodium stearyl fumerate, a stearate, talcum powder, a fatty acid, glycerol dibehenate, hexadecanoic acid, polyethylene glycol (PEG) and magnesium stearate.
  • the one or more gel forming agents comprises carbomer, wherein the carbomer is present in an amount from about 10 percent to about 60 percent by weight.
  • the one or more gel forming agents comprises carbomer, wherein the carbomer is present in an amount from about 20 percent to about 60 percent by weight.
  • the carbomer is present in an amount from about 40 percent to about 55 percent by weight.
  • carbomer is present in an amount from about 44 percent about 50 percent by weight.
  • the carbomer is present in an amount of about 44 percent by weight .
  • the carbomer is present in an amount of about 50 percent by weight .
  • the carbomer is present in an amount from about 20 percent to about 35 percent by weight.
  • the carbomer is present in an amount from about 25 percent to about 30 percent by weight.
  • the carbomer is present in an amount of about 27 percent by weight .
  • the carbomer is Carbopol 974P.
  • the one or more gel forming agents comprises hydroxypropylcellulose, wherein the hydroxypropylcellulose is present in an amount from about 1 percent to about 40 percent by weight.
  • the hydroxypropylcellulose is present in an amount from about 13 percent to about 30 percent by weight.
  • the hydroxypropylcellulose is present in an amount from about 13 percent to about 15 percent by weight. In one or more embodiments of the present invention, the hydroxypropylcellulose is present in an amount of about 14 percent by weight.
  • the hydroxypropylcellulose is present in an amount of about 15 percent by weight.
  • the hydroxypropylcellulose is present in an amount from about 25 percent to about 30 percent by weight.
  • the hydroxypropylcellulose is present in an amount of about 25 percent by weight.
  • the hydroxypropylcellulose is present in an amount of about 30 percent by weight.
  • the hydroxypropylcellulose is present in an amount from about 2 percent to about 10 percent by weight.
  • the hydroxypropylcellulose is present in an amount from about 6 percent to about 8 percent by weight.
  • the hydroxypropylcellulose is present in an amount of about 7 percent by weight.
  • the one or more gel forming agents comprises chitosan, wherein the chitosan is present in an amount from about 20 percent to about 60 percent by weight.
  • the chitosan is present in an amount from about 40 percent to about 50 percent by weight.
  • the chitosan is present in an amount from about 44 percent to about 45 percent by weight.
  • the chitosan is present in an amount of about 44 percent by weight .
  • the chitosan is present in an amount of about 45 percent by weight .
  • the one or more gel forming agents comprises thiolated chitosan, wherein the thiolated chitosan is present in an amount from about 20 percent to about 60 percent by weight.
  • the thiolated chitosan is present in an amount from about 40 percent to about 50 percent by weight.
  • the thiolated chitosan is present in an amount from about 44 percent to about 45 percent by weight.
  • the thiolated chitosan is present in an amount of about 44 percent by weight.
  • the thiolated chitosan is present in an amount of about 45 percent by weight.
  • the one or more gel forming agents comprises thiolated carbomer, wherein the thiolated carbomer is present in an amount from about 20 percent to about 60 percent by weight.
  • the thiolated carbomer is present in an amount from about 40 percent to about 55 percent by weight.
  • the thiolated carbomer is present in an amount from about 44 percent to about 50 percent by weight.
  • the thiolated carbomer is present in an amount of about 44 percent by weight.
  • the thiolated carbomer is present in an amount of about 45 percent by weight.
  • the tablet has a hardness of about 60 Newtons to about 150 Newtons .
  • the tablet has a hardness of about 60 Newtons to about 110 Newtons .
  • the tablet has a hardness of about 70 Newtons to about 120 Newtons .
  • the tablet has a hardness of about 70 Newtons to about 100 Newtons .
  • the tablet has a hardness of about 80 Newtons to about 90 Newtons . In one or more embodiments of the present invention, the tablet is a round flat tablet.
  • the tablet is a round biconvex tablet. In one or more embodiments of the present invention, the tablet has a diameter from about 6 mm to about 10 mm.
  • the tablet has a diameter of about 7 mm.
  • the tablet has a diameter of about 9 mm.
  • the tablet has a diameter of about 8 mm.
  • the tablet has a thickness of about 2.6 mm. In one or more embodiments of the present invention, the tablet contains from about 10 mg glatiramer acetate to about 100 mg glatiramer acetate.
  • the tablet contains from about 20 mg glatiramer acetate to about 40 mg glatiramer acetate.
  • the tablet contains about 20 mg glatiramer acetate.
  • the tablet contains about 40 mg glatiramer acetate. In one or more embodiments of the present invention, the tablet contains from about 40 mg glatiramer acetate to about 60 mg glatiramer acetate. In one or more embodiments of the present invention, the tablet contains about 50 mg glatiramer acetate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg carbomer, about 25 mg hydroxypropylcellulose, about 30.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 50 mg carbomer, about 15 mg hydroxypropylcellulose, about 12 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg chitosan, about 45 mg hydroxypropylcellulose, about 10.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 45 mg chitosan, about 30 mg hydroxypropylcellulose, about 2 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg thiolated chitosan, about 45 mg hydroxypropylcellulose, about 10.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 45 mg thiolated chitosan, about 30 mg hydroxypropylcellulose, about 2 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 40 mg glatiramer acetate, about 80 mg thiolated carbomer, about 25 mg hydroxypropylcellulose, about 30.5 mg mannitol, about 1.5 mg colloidal silicon dioxide and about 3 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 20 mg glatiramer acetate, about 50 mg thiolated carbomer, about 15 mg hydroxypropylcellulose, about 12 mg mannitol, about 1 mg colloidal silicon dioxide and about 2 mg sodium stearyl fumerate.
  • the present invention also provides an oral tablet comprising about 50 mg glatiramer acetate, about 40 mg carbomer, about 10 mg hydroxypropyl cellulose, about 47 mg mannitol, about 1 mg fumed silica and about 2 mg sodium stearyl fumerate.
  • the present invention also provides a method of delivering glatiramer acetate across a buccal membrane comprising orally administering an oral tablet of any one of the embodiments.
  • the tablet is placed between the cheek and gum.
  • the tablet is placed sublingually . In one or more embodiments of the present invention, the tablet is placed in the mouth at bedtime.
  • the present invention also provides a process of making a pharmaceutical composition containing glatiramer acetate, comprising the steps of: a) mixing the glatiramer acetate with one of more excipients under dry conditions; and b) forming the pharmaceutical composition.
  • the pharmaceutical composition is a buccal tablet.
  • step b) is performed by dry granulation.
  • step b) is performed by direct compression.
  • about 100 mg therefore includes the range 90-110 mg and therefore also includes 90, 91, 92, 93, 94, 95 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109 and 110 mg. Accordingly, about 100 mg includes, in an embodiment, 100 mg. It is understood that where a parameter range is provided, all integers within that range, tenths thereof, and hundredths thereof, are also provided by the invention.
  • 0.2-5 mg is a disclosure of 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg etc. up to 0.3 mg, 0.31 mg, 0.32 mg, 0.33 mg etc. up to 0.4 mg, 0.5 mg, 0.6 mg etc. up to 5.0 mg.
  • Tablet formulations Oral tablets containing 40 mg glatiramer acetate per tablet are prepared with the compositions set for the in Tables 1-4.
  • tablets are prepared as round flat tablets with a hardness of 60 - 150 Newtons.
  • Oral tablets containing 20 mg glatiramer acetate per tablet are prepared with the compositions set for the in Tables 5-8.
  • tablets are prepared as round flat tablets with a hardness of 60 - 150 Newtons.
  • Example 3 Oral tablets are prepared according to Examples 1-2, above or Example 7, below. A batch of oral tablets is stored at room temperature (about 25 °C) and under refrigeration (about 4 °C) . Samples from each batch are periodically examined for stability of the glatiramer acetate. The results demonstrate that glatiramer acetate stability in the oral tablets of the present invention is acceptable.
  • Example 4
  • Oral tablets are prepared according to Examples 1-2, above or Example 7, below. Oral tablets are placed on one side of a sample of porcine buccal tissue in a Franz cell according to Example 1, above. Media from the acceptor compartment on the other side of the buccal tissue is sampled and permeability of glatiramer acetate is assessed. The results demonstrate permeation of glatiramer acetate across a sample of buccal tissue .
  • Example 5
  • Oral tablets are prepared according to Examples 1-2, above or Example 7, below. Oral tablets are placed in apparatus 1 or apparatus 2 according to USP and dissolution of the drug is measured. After 3 hours the tablet is completely eroded. The results demonstrate that release of glatiramer acetate stability from the oral tablets of the present invention is acceptable .
  • Tablets were produced under dry conditions, e.g. direct compression or dry granulation / compaction. Tablets were prepared as small, flat, round disks approximately 8 mm in diameter and approximately 2.6 mm thick. A tablet was placed on glass under a small amount of water in order to simulate the conditions present in the buccal pouch. The tablet was observed to swell but stay solid; it did not fall apart. Over the course of two hours the thickness of the tablet remained, the diameter of the tablet was observed to shrink and a cloudy ring appeared around the tablet as it slowly eroded. Results are shown in Figure 1.
  • Porcine buccal tissue was obtained from a slaughterhouse. Immediately after slaughter of the pig, pieces bearing the buccal tissue were dissected from the cheek and stored in PBS pH 7.4 and cooled on ice. The buccal tissue was isolated from the inner cheek with a scalpel and used fresh. Subsequently, the suitability of the tissue biopsy was assessed. The exclusion criteria were tissue damage or scarring.
  • Freshly prepared buccal tissue was cut into stripes. Tissue sections with a thickness of approx. 700 - 800 ym were then prepared. The dermatome was applied to the buccal tissue surface and the tissue was cut with 24 mm punch. Permeation study
  • the cylindrical Franz cell is a diffusion chamber comprising an upper and a lower part between which the porcine buccal tissue was clamped. The two halves of the cell were held together by means of a ball and socket clamp.
  • the lower (acceptor) chamber has a volume of approx. 12 ml, while the volume of the upper (donor) chamber is variable.
  • the tissue specimens are punched out immediately prior to insertion in the Franz cells. The tissue is always inserted with the connective tissue (lamina propia and submucosa) facing downwards so that the mucosal epithelium layer is uppermost.
  • the medium temperature was adjusted to 37 °C and continuously stirred at a rate of 400 rpm.
  • the diffusion area of the porcine buccal tissue in the Franz cell was approx. 1.77 cm 2 .
  • Experiments were performed with six replicates for glatiramer acetate containing buccal tablets.
  • Buccal tablets were prepared as in Example 7 and were placed in the donor chamber of the Franz cells and the PBS buffer. The tablet was rinsed with the applied buffer in the Franz cell two or three times to ensure complete moisturizing of the tablet .
  • Permeation through the porcine buccal tissue into the acceptor medium was monitored over a period of 4 hours.
  • the acceptor medium was sampled at 6 different points of time (30, 60, 90, 120, 180 and 240 min) .
  • Table 9 shows results for the permeation studies described above. Table 9:
  • Figure 2 displays the average permeation of the different formulations. Tablets (diamond markers) , glatiramer acetate solution without pre-incubated tissue (square markers, solid line) and glatiramer acetate solution with DMSO pre-incubated tissue (square markers, dotted line) .
  • Copaxone ® is formulated as prefilled syringes containing 1 mL solution with 20 mg of glatiramer acetate.
  • glatiramer acetate becomes sticky and forms clots which interfere with formulation of the buccal tablets.
  • production of the tablets under dry conditions e.g. using direct compression or dry granulation / compaction, provides an effective solution to this problem and results in buccal tablets which effectively deliver glatiramer acetate across the buccal membrane and have favorable dissolution properties. See, Example 8 and Figure 1, above.

Abstract

La présente invention concerne un comprimé oral comportant de l'acétate de glatiramère en une quantité comprise entre environ 10 % et environ 60 % en poids et un ou des agent(s) gélifiant(s) en un total jusqu'à environ 90 % en poids. La présente invention concerne également un procédé d'administration d'acétate de glatiramère à travers une membrane buccale comprenant l'administration orale d'un comprimé oral selon un quelconque des modes de réalisation.
PCT/US2013/077034 2012-12-21 2013-12-20 Administration transmucosale d'acétate de glatiramère WO2014100639A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
CN201380067083.XA CN104869983A (zh) 2012-12-21 2013-12-20 醋酸格拉替雷的透粘膜给药
EA201591188A EA201591188A1 (ru) 2012-12-21 2013-12-20 Доставка глатирамера ацетата через слизистую оболочку
BR112015014095A BR112015014095A2 (pt) 2012-12-21 2013-12-20 entrega transmucosal de acetato de glatirâmero
SG11201504422XA SG11201504422XA (en) 2012-12-21 2013-12-20 Transmucosal delivery of glatiramer acetate
EP13865051.0A EP2934492A4 (fr) 2012-12-21 2013-12-20 Administration transmucosale d'acétate de glatiramère
CA2895359A CA2895359A1 (fr) 2012-12-21 2013-12-20 Administration transmucosale d'acetate de glatiramere
JP2015549792A JP2016503803A (ja) 2012-12-21 2013-12-20 酢酸グラチラマーの経粘膜送達
AU2013361053A AU2013361053A1 (en) 2012-12-21 2013-12-20 Transmucosal delivery of glatiramer acetate
US14/653,022 US20160193276A1 (en) 2012-12-21 2013-12-20 Transmucosal delivery of glatiramer acetate
KR1020157019729A KR20150111918A (ko) 2012-12-21 2013-12-20 글라티라머 아세테이트의 경점막 전달
MX2015007678A MX2015007678A (es) 2012-12-21 2013-12-20 Liberacion transmucosa de acetato de glatiramero por medio de tabletas orales.
IL239280A IL239280A0 (en) 2012-12-21 2015-06-08 Oral transmucosal transmission of glatiramer acetate
ZA2015/05049A ZA201505049B (en) 2012-12-21 2015-07-14 Transmucosal delivery of glatiramer acetate
HK16102020.2A HK1214134A1 (zh) 2012-12-21 2016-02-23 醋酸格拉替雷的透粘膜給藥
HK16102544.9A HK1214523A1 (zh) 2012-12-21 2016-03-07 醋酸格拉替雷的透粘膜給藥

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US201261745226P 2012-12-21 2012-12-21
US61/745,226 2012-12-21

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JP (1) JP2016503803A (fr)
KR (1) KR20150111918A (fr)
CN (1) CN104869983A (fr)
AU (1) AU2013361053A1 (fr)
BR (1) BR112015014095A2 (fr)
CA (1) CA2895359A1 (fr)
EA (1) EA201591188A1 (fr)
HK (2) HK1214134A1 (fr)
IL (1) IL239280A0 (fr)
MX (1) MX2015007678A (fr)
SG (1) SG11201504422XA (fr)
WO (1) WO2014100639A1 (fr)
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WO2015140790A1 (fr) 2014-03-17 2015-09-24 Mapi Pharma Ltd. Administration sublinguale d'acétate de glatiramère
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
WO2017138645A1 (fr) * 2016-02-12 2017-08-17 テイカ製薬株式会社 Matériau granulé à sec, préparation solide comprenant le matériau granulé à sec et son procédé de fabrication

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CN106924175B (zh) * 2015-12-29 2020-07-03 深圳翰宇药业股份有限公司 一种治疗多发性硬化症的药物组合物
JP2020525459A (ja) 2017-06-26 2020-08-27 アンスティテュ・パストゥール Ｈｉｖリザーバーを排除し、ウイルス負荷を低減する処置

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US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
WO2015140790A1 (fr) 2014-03-17 2015-09-24 Mapi Pharma Ltd. Administration sublinguale d'acétate de glatiramère
US10493122B2 (en) 2014-03-17 2019-12-03 Mapi Pharma Ltd. Sublingual delivery of glatiramer acetate
WO2017138645A1 (fr) * 2016-02-12 2017-08-17 テイカ製薬株式会社 Matériau granulé à sec, préparation solide comprenant le matériau granulé à sec et son procédé de fabrication

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KR20150111918A (ko) 2015-10-06
US20160193276A1 (en) 2016-07-07
IL239280A0 (en) 2015-07-30
EP2934492A1 (fr) 2015-10-28
EP2934492A4 (fr) 2016-08-17
ZA201505049B (en) 2016-10-26
SG11201504422XA (en) 2015-07-30
HK1214523A1 (zh) 2016-07-29
JP2016503803A (ja) 2016-02-08
CA2895359A1 (fr) 2014-06-26
AU2013361053A1 (en) 2015-07-30
EA201591188A1 (ru) 2016-04-29
BR112015014095A2 (pt) 2017-07-11
CN104869983A (zh) 2015-08-26
MX2015007678A (es) 2015-09-07
HK1214134A1 (zh) 2016-07-22

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